New evidence indicates that distinct mutations cause familial Parkinson's disease (PD) by mechanisms that may also operate in sporadic PD. These new data point to the importance of cell dysfunction preceding cell death and to the involvement of non-dopaminergic neurons in the disease. Accordingly, identifying mechanisms of cellular dysfunction that are common to multiple causes of PD may offer new therapeutic targets to halt or reverse the course of the disease. This renewal application for the UCLA UDALL Parkinson Disease Center of Excellence focuses on studies of progression of dysfunction, in complementary models expressing PD-causing mutations, and in a well characterized patient population. The center consists of 5 projects supported by an administrative core and a mouse genetics core. In the first three projects we propose to continue coordinated multidisciplinary work supported by the current award to characterize the progression of motor and non-motor behavioral anomalies and neuropathology (project 1), anomalies of neurotransmitter release (project 2) and of synaptic function (project 3) in genetic mouse models of PD, including novel models based on BAG technology. These projects will be complemented by the addition of cellular models (project 4) to analyze the mechanisms of cellular dysfunction leading to the phenotypes observed in the mouse. Studying progression of dysfunction will also be the focus of the new patient oriented component of the Center. In this project (project 5), we will conduct clinical longitudinal studies of disease phenotype after diagnosis, including psychiatric and cognitive co-morbidities. This will be coupled to the development and validation of an improved health-related quality of life assessment tool. These patient oriented studies will provide crucial clinical data for future analyses of genetic material from the same patients and for the translation of our basic research efforts into improved patient care. To identify the cellular alterations leading to neurodegeneration in PD, the UCLA UDALL Parkinson Disease Center of Excellence will focus on early manifestations of the disease occurring before the onset of motor symptoms and their progression. Integrating experimental models and clinical studies, the goal of our center is to understand the mechanisms of these cellular dysfunctions in order to spur the development of therapeutic strategies able to stop the disease process.